PROJECT SUMMARY Despite the fact that over 1 million Americans suffer from Geographic Atrophy (GA), there are no FDA approved therapies and only a limited understanding of the mechanisms that promote GA and the eventual associated blindness. There is an urgent need to fill in this gap in knowledge because doing so will open up new targets for pharmacological modulation that are so desperately needed to combat GA. Our long-term goal is to define the mechanisms by which non-protein-coding-RNA (ncRNA) is associated with infectious and immunological disease. Consistent with this goal, our overall objective here is to determine how the activity of DUSP11, an RNA tri-phosphatase associated with regulation of ncRNA, prevents immunological ocular disease. Our central hypothesis is that DUSP11 promotes select RNA interference (RNAi) activity, thereby controlling Alu transcript levels and preventing Alu-associated RPE pathology. The rationale for this proposed research is that, once it is known how the DUSP11 enzyme functions in the eye, new vertebrate models for human blindness can be developed and strategies for manipulating DUSP11 can be pursued, resulting in new and innovative approaches to the prevention and treatment of GA. We will test our central hypothesis and complete the objectives outlined in this proposal via the following two specific aims: 1) Determine how deficiency in Dusp11 affects RPE physiology and survival, and 2) Determine how DUSP11 contributes to select RNA interference and pathology in the RPE. Under the first aim, advanced imaging combined with histological and molecular assays will be utilized to determine how DUSP11 functions in the RPE. Comparing eyes from wild-type to Dusp11-/- mice, the applicants will assess altered transcripts and traits commonly associated with GA. Under the second aim, knockout and knockdown approaches combined with specialized RNA profiling techniques for mRNA and Alu-like SINE transcripts will be used to determine how the activity of DUSP11 affects multiple RNAi machineries and prevents RPE pathology. Our contribution here is expected to be a detailed understanding of how DUSP11 contributes to transposon control in the RPE and how decreased DUSP11 activity induces GA. This proposed research is significant because it is expected to have broad translational importance in the prevention and treatment of ocular diseases, especially GA. The proposed research is innovative, in the applicants' opinion, because it represents a new and substantive departure from the status quo by focusing on a factor that was previously unknown to be involved in mammalian RNAi or ocular disease. We expect the completion of this proposed work will provide sorely needed pharmacological targets for GA and a strong foundation for a research program focused on the activity of DUSP11 in RNAi, Alu transposon control, and ocular disease.